RESPONSE: Response to Seladelpar in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Control to or an Intolerance to Ursodeoxycholic Acid (UDCA)

Primary Biliary Cholangitis Clinical Trial

Official title:

RESPONSE: A Placebo-controlled, Randomized, Phase 3 Study to Evaluate the Efficacy and Safety of Seladelpar in Patients With Primary Biliary Cholangitis (PBC) and an Inadequate Response to or an Intolerance to Ursodeoxycholic Acid (UDCA)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04620733
• Other study ID #: CB8025-32048
• Status: Completed
• Phase: Phase 3
• Start date: April 21, 2021
• Est. completion date: August 11, 2023

Study information

• Verified date: September 2023
• Source: CymaBay Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To evaluate the treatment effect of seladelpar on composite biochemical improvement in cholestasis markers based on ALP and total bilirubin and to evaluate the safety of seladelpar over 12 months of treatment compared to placebo

Recruitment information / eligibility

• Status: Completed
• Enrollment: 193
• Est. completion date: August 11, 2023
• Est. primary completion date: August 11, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Must have given written informed consent (signed and dated) and any authorizations required by local law

2. 18 to 75 years old (inclusive)

3. Male or female with a definitive diagnosis of PBC

4. UDCA for the past 12 months (stable dose for >3 months prior to screening) OR intolerant to UDCA (last dose of UDCA >3 months prior to screening)

5. Laboratory parameters measured by the Central Laboratory at screening:

1. ALP =1.67× ULN

2. Aspartate aminotransferase (AST) =3× ULN

3. ALT =3× ULN

4. Total bilirubin =2× ULN

5. Estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease study equation)

6. International normalized ratio (INR) below 1.1× ULN For subjects on anticoagulation therapy, INR must be maintained in the range required for prophylaxis for their specific disease.

7. Platelet count =100×103/µL

NOTE: PT, INR, and platelets can be performed locally at the Screening Visit, if deemed necessary by the investigator after consultation with the medical monitor, in cases where centrally read samples are deemed invalid.

6. Females of reproductive potential must use at least 1 barrier contraceptive and a second effective birth control method during the study and for at least 90 days after the last dose. Male subjects who are sexually active with female partners of reproductive potential must use barrier contraception, and their female partners must use a second effective birth control method during the study and for at least 90 days after the last dose

Exclusion Criteria:

1. Previous exposure to seladelpar (MBX-8025).

2. A medical condition other than PBC that, in the investigator's opinion, would preclude full participation in the study (e.g., cancer) or confound its results (e.g., Paget's disease, any active infection).

3. Advanced PBC as defined by the Rotterdam criteria (albumin below the lower limit of normal AND total bilirubin above 1.0× ULN)

4. Presence of clinically important hepatic decompensation, including the following:

1. History of liver transplantation, current placement on liver transplantation list, or current Model for End-Stage Liver Disease (MELD) score =12. For subjects on anticoagulation medication, evaluation of the baseline INR, in concert with their current dose adjustments of their anticoagulant medication, will be taken into account when calculating the MELD score. This will be done in consultation with the medical monitor.

2. Complications of portal hypertension, including known esophageal varices, history of variceal bleeds or related interventions (ege.g., transjugular intrahepatic portosystemic shunt placement), ascites, and hepatic encephalopathy.

3. Cirrhosis with complications, including history or presence of spontaneous bacterial peritonitis, hepatocellular carcinoma, or hepatorenal syndrome.

5. Other chronic liver diseases:

1. Current features of AIH as determined by the investigator based on immunoserology, liver biochemistry, or historic confirmed liver histology.

2. PSC determined by the presence of diagnostic cholangiographic findings.

3. History or clinical evidence of alcoholic liver disease.

4. History or clinical evidence of alpha-1-antitrypsin deficiency.

5. History of biopsy confirmed NASH.

6. History or evidence of Gilbert's syndrome with elevated total bilirubin.

7. History or evidence of hemochromatosis.

8. Hepatitis B, defined as the presence of hepatitis B surface antigen.

9. Hepatitis C, defined as the presence of hepatitis C virus ribonucleic acid.

10. History, evidence, or high suspicion of hepatobiliary malignancy based on imaging, screening laboratory values, and/or clinical symptoms.

6. Known history of human immunodeficiency virus (HIV) or positive antibody test at screening

7. Clinically important alcohol consumption, defined as more than 2 drink units per day (equivalent to 20 g) in women and 3 drink units per day (equivalent to 30 g) in men, or inability to quantify alcohol intake reliably.

8. History of malignancy diagnosed or treated, actively or within 2 years, or ongoing evaluation for malignancy; localized treatment of squamous or noninvasive basal cell skin cancers and cervical carcinoma in situ is allowed if appropriately treated prior to screening.

9. Treatment with obeticholic acid (OCA) or fibrates (e.g., bezafibrate, fenofibrate, elafibranor, lanifibranor, pemafibrate, saroglitizar) 6 weeks prior to screening

10. Treatment with colchicine, methotrexate, azathioprine, or long-term systemic corticosteroids (>2 weeks) during 2 months prior to screening

11. Treatment with anti-pruritic drugs (e.g., cholestyramine, naltrexone, rifampicin, sertraline, or any experimental approach) must be on a stable dose within 1 month prior to screening

12. Treatment with any other investigational therapy or device within 30 days or within 5 half-lives, whichever is longer, prior to screening

13. For females, pregnancy or breastfeeding

14. Any other condition(s) that would compromise the safety of the subject or compromise the quality of the clinical study, as judged by the investigator

15. Immunosuppressant therapies

16. Other medications that effect liver or GI functions, such as absorption of medications or the roux-en-y gastric bypass procedure, may be prohibited and should be discussed with the medical monitor on a case-by-case basis.

17. Active COVID-19 infection during Screening.

Related Conditions & MeSH terms

• Cholangitis
• Liver Cirrhosis, Biliary
• Primary Biliary Cholangitis

Intervention

Drug:
• Seladelpar 10 mg
Seladelpar 10 mg one capsule daily for double-blind period, for a duration of up to 12 months
• Placebo
One capsule daily for double-blind period, for a duration of up to 12 months
• Seladelpar 5 mg
If down-titration needed, one capsule daily for double-blind period, for a duration of up to 12 months

Locations

Country	Name	City	State
Argentina	CINME (Centro de Investigaciones Metabolicas)	Buenos Aires
Argentina	Centro Medico Dra. De Salvo	Caba	Buenos Aires
Argentina	Hospital Italiano de Buenos Aires	Caba
Argentina	STAT Research S.A.	Ciudad Autonoma de Buenos Aire	Buenos Aires
Argentina	Hospital Italiano de La Plata	La Plata	Buenos Aires
Argentina	DIM CliniaPrivada	Ramos Mejía	Buenos Aires
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	Royal Brisbane & Women's Hospital	Herston	Queensland
Australia	Alfred Hospital	Melbourne	Victoria
Australia	The Royal Melbourne Hospital	Parkville	Victoria
Austria	Klinikum Wels-Grieskirchen GmbH, Abteilung Fur Innere Medizin I - Gastroenterologie	Wels
Belgium	UZ Antwerpen	Edegem	Antwerpen
Belgium	AZ Maria Middelares	Gent	Oost-Vlaanderen
Belgium	Universitair Ziekenhuis Gent	Gent	Oost-Vlaanderen
Belgium	Universitaire Ziekenhuizen Leuven	Leuven	Vlaams-Brabant
Belgium	CHU de Liège	Liege	Liège
Canada	London Health Sciences Centre	London	Ontario
Canada	University Health Network	Toronto	Ontario
Canada	Toronto Digestive Disease Associates Inc	Vaughan	Ontario
Chile	Centro Clinico Mediterraneo	La Serena	Coquimbo
Chile	Clinical Research Chile SpA	Valdivia	Los Ríos
Chile	Centro de Investigaciones Clínicas Vina del Mar	Valparaíso
Czechia	Fakultni nemocnice Ostrava- Interni a Kardiologicka Klinika, Oddeleni gastroenterologie, hepatologie a pankreatologie	Ostrava
Denmark	Aalborg Universitetshospital, Ambulatoriet for Medicinske Mave-Tarm Sygdomme	Aalborg
Denmark	Hvidovre Hospital	Hvidovre
France	CHU de Grenoble	Grenoble
France	Hopital de la Croix-Rousse	Lyon
France	Hopital Saint-Antoine - Service d'Hepato-Gastro-Enterologie -184, rue du Faubourg Saint-Antoine	Paris
Germany	Universitätsklinikum Bonn	Bonn	Nordrhein-Westfalen
Germany	Universitatsklinikum Erlangen, Medizinische Klinik I, Gastroenterologie	Erlangen
Germany	Universitatsklinikum Frankfurt. Medizinische Klinik I	Frankfurt am main
Germany	Ifi-Medizin GmbH	Hamburg
Germany	Gastroenterologische Gemeinschaftspraxis	Herne
Germany	Universitätsklinikum des Saarlandes	Homburg	Saarland
Germany	Universitatsklinikum Leipzig	Leipzig
Greece	Ippokrateio General Hospital of Athens	Athens	Attiki
Greece	General University Hospital of Larissa Department of Medicine and Research Laboratory of internal rv1edicine, National Expertise Center of Greece in Autoimmune liver Diseases	Larissa
Hungary	Semmelweis Egyetem	Budapest
Hungary	Somogy Megyei Kaposi Mor Oktato Korhaz	Kaposvár
Israel	Liver Unit	Jerusalem
Israel	Liver Disease Center, Sheba Medical Center	Ramat Gan
Israel	Institute for Digestive Tract & Liver Disease	Tel Aviv
Italy	Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona-Umberto I G.M. Lancisi G. Salesi	Ancona
Italy	Nuovo Ospedale Civile S. Agostino-Estense di Baggiovara	Bologna
Italy	Azienda Ospedaliero Universitaria Careggi	Firenze
Italy	ASST di Monza	Monza	MB
Italy	Azienda Ospedaliera Universita Padova	Padova
Italy	Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone	Palermo
Korea, Republic of	Soon Chun Hyang University Hospital Bucheon	Bucheon-si	Gyeonggido
Korea, Republic of	Inje University Busan Paik Hospital	Busan	Busan Gwangyeogsi
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Kyungpook National University Hospital	Daegu
Korea, Republic of	Seoul National University Bundang Hospital	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System - PPDS	Soeul
Mexico	Consultorio Medico - Distrito Federal	Ciudad de Mexico
Mexico	Consultorio de la Doctora Maria Sarai Gonzalez Huezo	Metepec
Mexico	Campeche No. 280, Int. 601 y 602, Col. Hipodromo, Cuauhtemoc	Mexico City
Mexico	Hospital Universitario Dr. Jose Eleuterio González	Monterrey
New Zealand	Gastroenterology, Christchurch Hospital	Christchurch	Canterbury
New Zealand	Gastroenterology Research Unit Dunedin Hospital	Dunedin	Otago
Poland	Uniwersyteckie Centrum Kliniczne Im.	Katowice
Poland	ID Clinic Akradiusz Pisula	Myslowice
Romania	Fundeni Clinical Institute	Bucharest
Russian Federation	Federal State Autonomous Educational Institution of Higher Education "Peoples' Friendship University of Russia", Centre of Liver Studies	Moscow
Russian Federation	State budget institution of healthcare of Moscow city "Moscow Clinical Scientific and Practical Centre n. a. A.S. Loginov" of Moscow City Healthcare, Department, Central Research Institute of Gastroenterology	Moscow
Russian Federation	Clinic of High Medical Technologies n.a. N.I. Pirogov	Saint Petersburg
Russian Federation	LLC Medical Company "Hepatolog"	Samara
Russian Federation	Stavropol state medical university	Stavropol
Russian Federation	Ulyanovsk Regional Clinical Hospital	Ulyanovsk
Spain	Hospital Universitario German Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Vall D'Hebron	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Virgen de la Victoria	Málaga	Malaga
Spain	Hospital Universitario Margues de Valdecilla	Santander	Cantabria
Switzerland	University of Zurich, Gastroenterology and Hepatology	Zürich
Turkey	Ankara Gazi University Faculty of Medicine Hospital	Ankara
Turkey	Ankara Sehir Hastanesi	Ankara
Turkey	Bezmi Alem University	Istanbul
Turkey	Marmara University Pendik Training and Research Hospital	Istanbul
Turkey	Ege University Medical Faculty	Izmir
Ukraine	Municipal Non-profit Enterprise "City Clinical Hospital #13" of Kharkiv City Council	Kharkiv
Ukraine	Medical Center OK!Clinic+LLC International Institute of Clinical Research	Kyiv
United Kingdom	University Hospitals Birmingham NHS Foundation Trust, Heritage Building (Queen Elizabeth Hospital)	Birmingham
United Kingdom	Hull Royal Infirmary	Hull
United Kingdom	Barts Health NHS Trust, Royal London Hospital, Ambrose King Centre	London	London, City Of
United Kingdom	Kings College Hospital	London
United Kingdom	Queen's Medical Centre	Nottingham	Nottinghamshire
United Kingdom	Gemini Clinical Trial Unit	Oxford	Oxfordshire
United Kingdom	University Hospitals Plymouth NHS Trust	Plymouth	Devon
United Kingdom	Portsmouth Hospitals NHS Trust	Portsmouth	Hampshire
United States	Digestive Healthcare of Georgia	Atlanta	Georgia
United States	Mercy Medical Center	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The Institute for Liver Health DBA Arizona Liver Health	Chandler	Arizona
United States	Galen Hepatology	Chattanooga	Tennessee
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Hospitals	Chicago	Illinois
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	The Liver Institute at Methodist Dallas Medical Center	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Texas Digestive Disease Consultants dba GI Alliance	Fort Hood	Texas
United States	Covenant Metabolic Specialists, LLC	Fort Myers	Florida
United States	Gastro One	Germantown	Tennessee
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Baylor College of Medicine	Houston	Texas
United States	Southern Therapy and Advanced Research, LLC (STAR)	Jackson	Mississippi
United States	Florida Research Institute	Lakewood Ranch	Florida
United States	Arkansas Diagnostic Center	Little Rock	Arkansas
United States	Care Access Research - Lumberton	Lumberton	North Carolina
United States	MNGI Digestive Health, P.A.	Maplewood	Minnesota
United States	Schiff Center for Liver Diseases/University of Miami	Miami	Florida
United States	Vanderbilt Digestive Disease Center	Nashville	Tennessee
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	NYU Langone Health / NYU Grossman School of Medicine	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Henry Ford Health System	Novi	Michigan
United States	Stanford University School of Medicine	Palo Alto	California
United States	California Liver Research Institute	Pasadena	California
United States	UPMC Center for Liver Diseases	Pittsburgh	Pennsylvania
United States	Bon Secours Richmond Community Hospital LLC	Richmond	Virginia
United States	University of Rochester Medical Center	Rochester	New York
United States	University of California, Davis Medical Center	Sacramento	California
United States	Saint Louis University	Saint Louis	Missouri
United States	American Research Corporation at the Texas Liver Institute	San Antonio	Texas
United States	Pinnacle Clinical Research, PLLC	San Antonio	Texas
United States	California Pacific Medical Center - Sutter Pacific Medical Foundation	San Francisco	California
United States	Covenant Research and Clinics, LLC	Sarasota	Florida
United States	Liver Institute Northwest	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
CymaBay Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Canada,  Chile,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Korea, Republic of,  Mexico,  New Zealand,  Poland,  Romania,  Russian Federation,  Spain,  Switzerland,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite endpoint of ALP and total bilirubin	ALP < 1.67× ULN,; = 15% decrease in ALP, and; Total bilirubin =1.0× ULN	12 months
Secondary	Normalization of ALP	Proportion of subjects with ALP =1.0× ULN	12 months
Secondary	Change in baseline numerical rating scale (NRS)	Weekly averaged pruritus NRS in subjects with baseline NRS =4. The NRS is a scale of 0 (no itching) to 10 (worst imaginable itching)	6 months